The overall purpose of this proposal is to examine the role of the estrogen receptor, a nuclear transcription factor, in the differentiation of cerebral cortical circuitry that subserves cognition and undergoes a period of naturally occurring cell death, with features characteristics of apoptosis. The proposed experiments examine the interactions of the estrogen receptor with a family of growth factors, the neurotrophins, in the regulation of this neuronal death within the developing rodent prefrontal/limbic cerebral cortex. We hypothesized that this transcription factor, activated by endogenous growth factors, may selectively alter the process of naturally occurring cell death, and under conditions of inappropriate activation, lead to altered patterns of cortical differentiation. The first specific aim will be to determine whether estrogen receptors mediate the neurotrophin regulation of apoptosis in the developing rodent prefrontal/limbic cerebral cortex. The experimental design will make use of an in vitro explant culture model of chemically induced apoptosis and a complementary in vivo model of naturally occurring apoptosis. The second specific aim will be to determine estrogen receptor-dependent components of the cellular signaling pathway that initiates apoptotic cell death in the cerebral cortex. Specifically, experiments will investigate the estrogen receptor-mediated regulation of specific cyto-protective (i.e., Bcl-2 and Bcl-x) and cytotoxic (TNFr, p75 and fas) components of the signaling pathway that mediate cell survival using in vitro and complementary in vivo models of naturally occurring apoptosis in the developing limbic/prefrontal cerebral cortex. The answers to these questions have clinical implications. Altered activation of transcription factors in the immature cerebral cortex may lead to inappropriate patterns of neuronal survival and differentiation and impairments in the development of cognitive and affective behaviors. Such perturbations may be an important etiologic feature of the impaired functioning characteristics of a variety of psychiatric disorders including schizophrenia and pediatric dementias. Elucidation of basic developmental processes is essential to understanding the pathogenesis of these important psychiatric disorders. Additionally, these experiments will provide a framework for future studies examining the role of the estrogen receptor in cortical plasticity and in the formation of cognitive circuits, integrating the cerebral cortex with its efferent targets.